Tablet manufacturing method and tablet

ABSTRACT

According to the tablet production method of the present invention, tablet is produced by compressing molding material by means of punches and dies comprising the steps of using powdered or granular material including compound which is denaturalized or inactivated when tabletted at high pressure is used as the molding material, housing the punches and the dies in a spraying chamber, generating pulsating vibration air and spraying lubricant mixed in air in the spraying chamber, applying the lubricant on the surfaces of the punches and the dies while the lubricant sprayed in the spraying chamber is mixed with the pulsating vibration air, and tabletting the molding material by means of the punches applied with the lubricant on the surface thereof and the dies applied with the lubricant on the surface thereof.

TECHNICAL FIELD

The present invention relates to a tablet production method,particularly to a tablet production method wherein a tablet includingcompound powdered or granulated which is apt to be denaturalized orinactivated when tabletted at high pressure can be manufactured withoutdenaturalizing or deactivating drugs and also to a tablet productionmethod wherein a tablet including solid dispersion powdered orgranulated can be manufactured while keeping the function of the soliddispersion powdered or granulated.

The present invention also relates to a tablet including compoundpowdered or granulated which is denaturalized or inactivated whentabletted at high pressure without denaturalized or inactivated and alsoto a tablet including solid dispersion powdered or granulated keepingthe function thereof.

BACKGROUND ART

A tablet has an advantage of easy dosing and is the most preferable typefor patient as oral administration and intrabuccal administration.

Such a tablet is generally produced by an internal lubricant method andan external lubricant spraying method.

According to the internal lubricant method, in order to prevent thatmolding material to be tabletted is apt to attach on punches and diesand gride between the punches and dies is apt to be caused so as toexecute smooth tabletting and also prevent defective goods withsticking, capping or laminating, magnesium stearate, lauryl sodiumsulphate, talc and so on are mixed in the molding material to betabletted other than active compound and diluting agent and the mixtureis compressed to obtain a tablet.

As an external lubricant spraying method, a tablet production method hasbeen disclosed in, for example, JP-B-41-11273 and JP-A-56-14098.

FIG. 17 schematically shows procedures of the tablet production methoddisclosed in JP-B-41-11273.

According to the method comprised of charging a fixed amount of materialto be tabletted in a die, tabletting the charged material in the die bymeans of a pair of an upper and a lower punches, and discharging thetablet, as a procedure before molding material is charged in the die 151as shown in FIG. 17( a), a spray nozzle 159 for spraying lubricant L isprovided above the die 151 and lubricant L is applied on a lower surface153 s of the upper punch 153 and an upper surface 154 s of the lowerpunch 154, both of which are provided for the die 151 which comes to aplace where the spray nozzle 159 is placed. Then molding material ischarged in the die 151 as shown in FIG. 17( b), and the charged materialm is compressed by means of the upper punch 153 on which lower surface153 s is applied with lubricant L and the lower punch 154 of which uppersurface 154 s is applied with lubricant as shown in FIG. 17( c).

The member indicated by the numeral 152 in FIG. 17 shows a rotary tableprovided with the die 151 (The same numeral is used in FIG. 18).

FIG. 18 shows a tablet production method described in JP-A-56-14098.

According to this method, before molding material is charged in a die151, a spray 156 for spraying lubricant L and a nozzle 159 for sprayingair are provided above the die 151. Lubricant L is sprayed in the spray156 when the die 151 comes where the spray 156 is provided as shown inFIG. 18( a), lubricant is applied on an upper surface 154 s of a lowerpunch 154 provided for the die 151 as shown in FIG. 18( b). As shown inFIG. 18( c), compressed air is sprayed on the lower punch 154 at aposition where the nozzle 159 is provided, lubricant L applied on theupper surface 154 s of the lower punch 154 is blown upwardly to bedispersed, then the dispersed lubricant L is attached on an inner wall151 s of the die 151 and a lower surface 153 s of an upper punch 153.Thereafter, molding material m is compressed to produce a tablet bymeans of lubricated inner wall 151 s of the die 151, lubricated lowersurface 153 s of the upper punch 153, and lubricated upper surface 154 sof the lower punch 154.

However, some drugs are destabilized or dissolved or its elution becomesslow because its crystal is deformed by the pressure applied at the timeof tabletting (usually 1 ton/c m²–2 ton/c m²), friction, and heating.(Hereinafter such substances are called “drugs which is denaturalized orinactivated when tabletted at high pressure” in this specification.)

As a method for tabletting such drugs, an internal lubricant methodwherein lubricant such as macrogol 6000, sucrose esters of fatty acid,and so on are added to molding material has been already suggested.(Refer to the summary of 11^(th) pharmaceuticals and powder designsymposium, 79 (1994) and JP-A-8-175996.)

Solid dispersing pharmaceuticals wherein compound is dispersed in lowmolecular carrier or high molecular carrier has been recently developed.

Such solid dispersing pharmaceuticals are highly effective to heightensolubility of drugs which is slight soluble and has low absorbabilityinto the body in case of oral dosage, to control releasing speed ofdrugs, and to improve bioavailability of drugs.

Solid dispersion pharmaceuticals are generally produced by a fusionmethod wherein drugs and carrier are heated and fused and thereaftercooled down. Or they are produced by means of a solvent method whereindrugs and carrier are dissolved in an appropriate solvent and thesolvent is removed. Or they are produced by a fusion-solvent methodwherein a fusion method and a solvent method are combined.

However, an internal lubricant means wherein a tablet including compoundwhich are denaturalized or inactivated when tabletted at high pressureis produced by adding lubricant such as macrogol 6000, sucrose esters offatty acid, and so on in molding material isn't an adequate method.According to drugs, compressed tablet may be destabilized or decomposed,or elution may become slow even if lubricant such as macrogol 6000,sucrose esters of fatty acid, and so on is added to molding material.

Further, depending on drugs, they may attach on punches and dies at thetime of tabletting. As the result, produced tablet may cause sticking,capping and laminating.

When solid dispersion is produced into a tablet as solid dispersingpharmaceuticals wherein solid dispersion is pulverized into a suitableparticle size and the pulverized substance and lubricant are mixedaccording to the prior internal lubricant method, property of the soliddispersion tablet may be changed because of water repellency oflubricant included in the tablet. When lubricant is included in thetablet, high pressure is required to give practical hardness. However,the solid dispersion may be denaturalized because of high tablettingpressure and originally designed property (for example disintegratingtime) isn't achieved.

Therefore, pharmaceuticals including drugs which are denaturalized orinactivated when tabletted at high pressure and solid dispersingpharmaceuticals are generally supplied as capsule in the market so far.

However, capsule is hard to be taken for elderly person and childrenbecause it floats on the water when taking with water. It has beenrequested by physician and so on to develop a tablet which sinks in thewater and is easy to be swallowed when taking with water aspharmaceuticals including drugs which are denaturalized or inactivatedwhen tabletted at high pressure and as solid dispersing pharmaceuticals.

Also capsule needs a body and a cap and its production takes a lot oflabor as follows. Drugs which are denaturalized or in activated whentabletted a thigh-pressure and solid dispersion (powder and granule) arepulverized and charged in the body of capsule and the cap is coveredthereon to be sealed.

Further, physician requests not only that pharmaceuticals conventionallysupplied as capsule in the market is produced as a tablet but also thatsuch tablet is dividable so that patient can take appropriate dosage.

The present invention has been developed in order to solve theabove-mentioned problems. The object of the present invention is toprovide a production method of tablet wherein a tablet includingcompound powdered or granulated which is denaturalized or inactivatedwhen tabletted at high pressure can be easily produced withoutdenaturalizing or deactivating such compound.

Another objet of the invention is to provide a tablet including soliddispersion powdered or granulated keeping function of the soliddispersing material, a tablet including compound which is denaturalizedor inactivated when tabletted at high pressure without denaturalizing ordeactivating such compound, and a dividable type tablet of these tabletswhich can keep its function when divided.

DISCLOSURE OF THE INVENTION

The tablet production method in the present invention is a tablettingmethod for compressing molding material by means of punches and dies.Powdered or granular material including compound which is denaturalizedor inactivated when tabletted at high pressure is used as the moldingmaterial. The punches and the dies are housed in a spraying chamber.Pulsating vibration air is generated, and lubricant mixed in air issprayed in the spraying chamber. The surfaces of punches and dies areapplied with lubricant while lubricant sprayed in the spraying chamberis mixed with pulsating vibration air. Then molding material istabletted by means of the punches and dies applied with the lubricant onthe surface thereon.

Here in this specification “high pressure” means a required tablettingpressure for compressing molding material by an internal lubricantmethod and for producing a tablet having practical hardness. Morespecifically it means greater than or equal to 1 ton/cm².

“Compound powdered or granulated which is denaturalized or inactivatedwhen tabletted at high pressure” means powdered and granule of compoundwhich is apt to be denaturalized or inactivated when tabletted by meansof an internal lubricant method. Specifically the examples of suchcompound are pharmaceuticals shown in the following tables 3–6,explained hereinafter.

“Powdered or granular material including compound powdered or granulatedwhich is denaturalized or inactivated when tabletted at high pressure”may include diluting agent, binder, supplement such as solutionadjuvant, solubilizer and disintegrant, corrigent, colorant, adjuvantfor pharmaceuticals, antioxidant, preservative, opacifying agent, chargeprotector, aroma, sweetening agent, fluidizing agent, flavoring agent,and so on, if required, other than compound powdered or granulated whichis denaturalized or inactivated when tabletted at high pressure.However, it doesn't include lubricant.

According to this production method, lubricant is sprayed in thespraying chamber wherein pulsating vibration air is generated andlubricant mixed with pulsating vibration air is applied on the surfacesof punches and dies. Comparing with prior external lubricant sprayingmethod, lubricant can be uniformly applied on the surfaces of thepunches and dies.

As a result, under the process wherein compound which is denaturalizedor inactivated when tabletted at high pressure is tabletted, thecompound is hard to be attached on the surfaces of the punches and diesso that such tablet as biochemical pharmaceuticals is produced withoutsticking, capping and laminating.

Moreover, lubricant is merely attached on the surface of tablet andisn't included inside of tablet. Therefore, comparing with a tabletincluding lubricant, produced tablet has practical hardness even ifcompound powdered or granulated which is denaturalized or inactivatedwhen tabletted at high pressure is tabletted at low pressure (concretelyunder 1 ton/c m².

Several kinds of lubricant can be used for tablet production method ofthe present invention. Lubricant isn't specifically limited, forexample, there are stearate acid metal salt (magnesium stearate, calciumstearate and so on), stearic acid, sodium lauryl sulfate, sodium laurylmagnesium, powdered gum arabic, carnauba wax, anhydrous silicic acid,magnesium oxide, silic acid hydrate, boric acid, fatty acid sodium salt,leucine, and so on which have been commonly used. One of them may beused solely or more than two of them may be combined.

As for diluting agent, there are several kinds, such as saccharides(lactose, sucrose, glucose, mannitol, and so on), starch (for example,potato, wheat, corn and so on), inorganic substance (calcium carbonate,calcium sulfate, sodium bicarbonate, sodium chloride, and soon),crystalline cellulose, powdered plant (powdered glycyrrhiza, powderedgentian, and so on).

Moreover, any kind of pulsating vibration air with different cycle andstrength, regardless of positive pressure or negative pressure, may beused if air pressure of pulsating vibration air can achieve function offorcibly diffusing lubricant particle sprayed in the sampling chamber bygenerating air vibration all over the sampling chamber.

Conditions such as frequency and pressure of pulsating vibration airdepend on size and shape of punches and dies of a tabletting machine,size and shape of a spraying chamber, how a lubricant spraying means isprovided, and description of active compound. Therefore, conditionscan't be simply defined and is defined based on experiments.

According to a preferred tablet production method, molding material iscompressed by means of punches and dies. The method uses soliddispersion powdered or granulated molding material. The punches and thedies are housed in a spraying chamber, pulsating vibration air isgenerated therein, and lubricant mixed in air is sprayed. The lubricantis applied on the surfaces of the punches and the dies while thelubricant sprayed in the spraying chamber is mixed with the pulsatingvibration air and the molding material is tabletted by the lubricatedpunches and the lubricated dies.

“Solid dispersion powdered or granulated” in this specification meanssolid dispersion (powder or granule) ground into appropriate particlesize.

More concretely explained, this tablet production method is effectivefor tabletting solid dispersion powdered or granulated including lowmolecule compounds of which elution is delayed and high moleculecompounds which is apt to be dissolved and denaturalized when tablettedat high pressure according to an internal lubricant method.

As a carrier of solid dispersion, so called high molecule carrier can beused.

Generally there are pH dependent high molecular carrier, pH independenthigh molecular carrier, water-soluble high molecular carrier, and so on.Examples are as follows:

-   -   hydroxypropylmethylcellulose phthalate 220824 (HP50),        hydroxypropylmethylcellulose phthalate 220731 (HP55),        hydroxypropylmethylcellulose acetate succinate (A coat),        carboxymethylethylcellulose (CMBC), cellulose acetate phthalate        (CAP), metaacrylic acid copolymer LD (L30D55), meta acrylic acid        copolymer S(S-100), aminoalkylmetaacylate copolymer E (soluble        in stomach), polyvinyl acetal diethyl amino acetate (ABA),        polyvinylpyrrolidone (K-25, 30, 90; PVP), ethyl cellulose (BC),        metacrylic acid copolymer RS (RS30D), polyvinyl alcohol (PVA),        metylcellulose (MC), hydroxypropylcellulose (HPC),        hydroxypropylmethylcellulose 2208 (METROSE 90SH),        hydroxypropylmethylcellulose 2906 (METOLOSE 65SH),        hydroxypropylmethylcellulose 2910 (METROLSE 60SH, TC-5R), sodium        carboxymethylcellulose, dextrin, pullulane, gum arabic,        tragacanth, propylene glocol alginate, agar powder, gelatin,        starch, processed starch, phospholipid (lecithin), glucomannnan        glucomannnan, and so on.

Such high molecular carrier may be used solely or some of them may becombined if required.

Particle size of high molecular carrier is usually less than or equal to7000 μm, more preferably less than or equal to 2000 μm. Conditions suchas pressure, temperature, supplying speed, adding amount and supplyingspeed of water or plasticizer, and so on, according to the presentinvention, differ depending on the kind of used drugs, high molecularcarrier, dual-axis extruder, and so on. However, it is important tocombine them so as to lower molding temperature under decompositiontemperature of drugs and high molecular carrier. And it is alsoimportant to change them according to product characteristic expected tobe produced.

The ratio (weight ratio) when drugs and high molecular carrier are mixeddiffers depending on kinds, object, membrane characteristic, and so onthereof. It is suitable at 0.1–999 of high molecular carrier for 1 drug,preferably 0.5–500, more preferably 1–50.

In a material including both compound which is unstable for heat andhigh molecular carrier, water solution or dispersant of plasticizer canbe added to the material when or before the material is extruded withthe dual-axis extruder. When this method is utilized, temperature oftransition of high molecular carrier can be lowered. Therefore, moldingtemperature can be lower than the decomposition temperature of compoundand high molecular carrier so that decomposition caused by the heat ofdrugs and high molecular carrier can be prevented. Of course, in amaterial which doesn't include both compound which is unstable for heatand high molecular carrier, water solution or dispersant of plasticizercan be added in a same manner.

As plasticizer for lowering the temperature of transition of highmolecular carrier, compound which has been used as plasticizer for filmcoating in the field of manufacturing technique can be used. Such acompound is as follows;

-   -   cetanol, fatty acid polyoxyethylene-polyoxyp, macrogol (200,        300, 400, 600, 1000, 1500, 1540, 4000, 6000, 20000), triacetyne,        triethyl citric (cytroflex), and so on.

Adding amount of plasticizer depends on used drugs and high molecularcarrier, however its ratio is suitable at 1%–80% for a molecularcarrier, preferably at 5%–50%.

Plasticizer may be directly added to the mixture of high molecularcarrier and drugs at first or plasticizer dissolved or deipersed in thewater may be added during molding. Adding method of platicizer isn'tlimited.

According to this tablet production method, lubricant is sprayed in thespraying chamber wherein pulsating vibration air is generated and thelubricant mixed with pulsating vibration air is applied on the surfacesof punches and dies. Therefore, lubricant can be applied uniformly onthe surfaces of the punches and dies comparing with the prior externallubricant spraying means.

As the result, molding material hardly attaches on the surfaces ofpunches and dies in tabletting step of solid dispersion powdered orgranulated so that produced tablet of solid dispersion doesn't causesticking, capping and laminating.

Further, lubricant is attached only on the surface of produced tablet ofsolid dispersion and isn't included therein. Therefore, produced tabletof solid dispersion has practical hardness even if solid dispersionpowdered or granulated is tabletted at low tabletting pressure comparingwith a tablet of solid dispersion including lubricant therein.

According to this tablet production method, tablet of solid dispersionsubstance can be tabletted at low tabletting pressure so that propertyof solid dispersion substance isn't changed.

According to the tablet production method for compressing moldingmaterial by means of punches and dies, powdered or granular material,including compound which is denaturalized or inactivated when tablettedat high pressure, is used as molding material. The punches and the diesare housed in a spraying chamber, the lubricant is applied on thesurfaces of the punches and the dies while the lubricant sprayed in thespraying chamber is mixed with positive pulsating vibration air, and themolding material is tabletted by the punches applied with the lubricanton the surface thereof, and the dies applied with the lubricant on thesurface thereof.

According to this production method, lubricant mixed with positivepulsating vibration air is sprayed in the spraying chamber and isapplied on the surfaces of the punches and dies. Lubricant can beuniformly applied on the surfaces of the punches and dies comparing withthe prior external lubricant spraying method.

As a result, when tabletting compound powdered or granulated which isdenaturalized or inactivated when tabletted at high pressure, suchcompound as denaturalized or inactivated when tabletted at high pressurehardly attaches on the surface of the punches and dies and producedbiological pharmaceuticals doesn't cause sticking, capping, laminating,and so on.

Further, lubricant is attached only on the surfaces of tablet and isn'tincluded therein. Produced tablet has practical hardness even ifcompound which is denaturalized or inactivated when tabletted at highpressure is tabletted at low tabletting pressure (concretely less thanor equal to 1 ton/cm²) comparing with the tablet including lubricant.

According to another tablet production method for compressing moldingmaterial by means of punches and dies, solid dispersion powdered orgranulated material is used for molding. The punches and the dies arehoused in a spraying chamber, lubricant is applied on the surfaces ofthe punches and the dies while the lubricant sprayed in the sprayingchamber is mixed with positive pulsating vibration air, and the moldingmaterial is tabletted by the punches applied with the lubricant on thesurface thereof, and the dies applied with the lubricant on the surfacethereof.

According to this method, lubricant mixed with positive pulsatingvibration air is sprayed in the spraying chamber and the mixed lubricantis applied on the surfaces of the punches and dies. Therefore, lubricantcan be uniformly applied on the surfaces of the punches and diescomparing with the prior external lubricant spraying means.

As the result, molding material hardly attaches on the surfaces of thepunches and dies when solid dispersion powdered or granulated istabletted and produced tablet of solid dispersion doesn't causesticking, capping, laminating and so on.

Further lubricant is attached only on the surface of produced tablet ofsolid dispersion and isn't included therein. Therefore, the producedtablet of solid dispersion has a hardness of practical level even ifsolid dispersion powdered or granulated is compressed at low tablettingpressure comparing with the tablet of solid dispersion includinglubricant therein.

According to this tablet production method, solid dispersion can betabletted at low tabletting pressure so that property of soliddispersion isn't changed.

According to the tablet production method, spraying amount per tablet inthe sampling chamber is preferably greater than or equal to 0.0001weight percent and less than or equal to 0.2 weight percent.

The amount of lubricant is preferably reduced as far as possible inorder to prevent disintegration time of tablet from extending and toprevent hardness of tablet from lowering. The amount of lubricant pertablet is preferably greater than or equal to 0.0001 weight % and lessthan or equal to 0.2 weight %, more preferably greater than or equal to0.01 weight % and less than or equal to 0.1 weight %.

According to this production method, lubricant amount per tablet is setgreater than or equal to 0.0001 weight % and less than or equal to 0.2weight %. Therefore disintegration time of tablet doesn't extend andhardness of tablet doesn't deteriorated.

According to the tablet production method, the punches may be providedwith a projected line for dividing of a tablet.

In this tablet production method, the punches are provided with aprojected line for forming a dividing line of a tablet so that adividable tablet including powdered or granular compound which isdenaturalized or inactivated when tabletted at high pressure and adividable tablet including solid dispersion powdered or granulated ofwhich function isn't damaged.

The tablet production method is desirably characterized in that thefollowing steps are continuously executed; housing the punches and thedies in the sampling chamber; generating pulsating vibration air,spraying lubricant mixed in air in the spraying chamber, and applyingthe lubricant on the surfaces of the punches and the dies while thelubricant sprayed in the spraying chamber is mixed with the pulsatingvibration air, and tabletting the molding material by the punchesapplied with the lubricant on the surface thereof and the dies appliedwith the lubricant on the surface thereof.

According to this method, tabletting is continuously executed utilizingthe fact that sticking isn't caused. A tablet including compoundpowdered or granulated which is denaturalized or inactivated whentabletted at high pressure can be produced at industrial productionbase.

The tablet production method is further characterized in that thefollowing procedures are continuously executed; housing the punches andthe dies in the spraying chamber; applying the lubricant on the surfacesof the punches and the dies while the lubricant sprayed in the sprayingchamber is mixed with the positive pulsating vibration air; andtabletting the molding material of the punches applied with thelubricant on the surface thereof, and the dies applied with thelubricant on the surface thereof.

According to this method, tabletting is continuously executed utilizingthe fact that sticking isn't caused. A tablet including solid dispersionpowdered or granulated can be produced at industrial production base.

The tablet production method may be characterized in that tablettingpressure for the molding compound by the punches applied with thelubricant on the surface thereof and the dies applied with the lubricanton the surface thereof is reduced.

Herein “low pressure” means that tabletting pressure is lower comparingwith the prior internal lubricant method and the prior externallubricant spraying method. More concretely explained, this tabletproduction method can produce a tablet having enough practical levelhardness even if its tabletting pressure is less than or equal to 1ton/cm².

According to this tablet production method, tabletting pressure formolding material is low. Even if the granule included in the tablet ispowdered or granular material including compound powdered or granulatedwhich is denaturalized or inactivated when tabletted at high pressure,such material can be tabletted without denaturalizing or deactivatingthe compound.

Further, even if granule to be included in the tablet is soliddispersion powdered or granulated, such material can be tablettedwithout destroying the function thereof.

The tablet includes granule containing active agent in diluting agentand lubricant only on the surface thereof and the granule is compoundpowdered or granulated which is denaturalized or inactivated whentabletted at high pressure.

The tablet has lubricant only on the surface thereof so that delay oftablet disintegration time, which is caused by water repellency oflubricant, isn't happened.

Further, this tablet includes lubricant therein so that it can betabletted at low tabletting pressure. As a result, compound powdered orgranulated which is denaturalized or inactivated when tabletted at highpressure isn't denaturalized or inactivated.

The tablet includes granule containing active agent in diluting agentand lubricant only on the surface thereof, and the granule is soliddispersion powdered or granulated.

Such a tablet is provided with lubricant only on its surface so thatdisintegration time of the tablet, which may be caused by repellency oflubricant, doesn't delay.

Further, the tablet doesn't include lubricant therein so that it can betabletted at low pressure and the function of solid dispersion powderedor granulated isn't damaged.

Accordingly, the lubricant amount per tablet is preferably greater thanor equal to 0.0001 weight percent and less than or equal to 0.2 weightpercent.

Such a tablet is provided with minute amount of lubricant on its surfaceso that disintegration time delay of the tablet, which may be caused byrepellency of lubricant, doesn't happen.

Therefore, when this tablet is used as an uncoated tablet, it becomes arapidly soluble tablet. It is desirable when a tablet is required to berapidly disintegrated at an objected place like an intraorally rapidlydisintegrable tablet. Further, if the tablet surface is coated with afilm which is dissolved at the objective place, the tablet is rapidlydissolved at the objective place when the coated film is dissolved sothat such a tablet can be preferably used as a tablet expected to bedissolved at the objective place.

“Anomalous” in this specification means shapes except for round, forexample, track (capsule), rugby ball, polygon such as triangle,rectangle, pentagon, and so on, diamond, almond, bombshell, half moon,heart, star, and so on.

Because a tablet has anomalous shape, contained drugs (active agent) canbe easily distinguished according to these shapes. As a result, such atablet doesn't have a fear of medication error.

The tablet is characterized as having a dividing line on the surfacethereof.

According to such a tablet, a tablet which is soluble at a desired placeand is also dividable can be provided in the market.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 schematically shows a sectional view of an enlarged substantialpart of one embodiment of an external lubricant spraying type tablettingmachine used in the tablet production method of the present invention.

FIG. 2 is a schematic section of the external lubricant spraying typetabletting machine shown in FIG. 1.

FIG. 3 schematically shows a substantial part of the external lubricantspraying type tabletting machine shown in FIG. 1. FIG. 3( a) is aschematic section of the external lubricant spraying type tablettingmachine according to the present invention. FIG. 3( b) is a schematicsection around the pulsating vibration air generation means.

FIG. 4 explains a concrete example of pulsating vibration air, FIG. 4(a) and FIG. 4( b) show negative pulsating vibration air respectively.

FIG. 5 schematically shows other embodiment of the external lubricantspraying type tabletting machine used for the tablet production methodof the present invention. FIG. 5( a) is a schematic section of anenlarged substantial part of the external lubricant spraying typetabletting machine of the present invention and FIG. 5( b) is aschematic sectional view around pulsating vibration air generationmeans.

FIG. 6 explains a concrete example of pulsating vibration air. FIG. 6(a) and FIG. 6( b) show positive vibration air respectively.

FIG. 7 schematically explains many kinds of tablets produced inexperiments. A schematic plane view of each tablet is shown at left andits schematic side view is shown at right.

FIG. 8 schematically explains many kinds of tablets produced inexperiments. A schematic plane view of each tablet is shown at left andits schematic side view is shown at right.

FIG. 9 schematically explains many kinds of tablets produced inexperiments. A schematic plane view of each tablet is shown at left andits schematic side view is shown at right.

FIG. 10 schematically explains many kinds of tablets produced inexperiments. A schematic plane view of each tablet is shown at left andits schematic side view is shown at right.

FIG. 11 schematically explains many kinds of tablets produced inexperiments. A schematic plane view of each tablet is shown at left andits schematic side view is shown at right.

FIG. 12 schematically shows a sectional view of means (metering feeder)for quantitatively supplying molding lubricant contained in a hopperinto a conduit.

FIG. 13 is a plane view schematically showing one embodiment of anelastic membrane used for the means (metering feeder) in FIG. 12.

FIG. 14 schematically shows operations of the means (metering feeder)shown in FIG. 12.

FIG. 15 is a plane view schematically showing another embodiment of anelastic membrane used for the means (metering feeder) in FIG. 12.

FIG. 16 is a sectional view schematically showing another embodiment ofpulsating vibration air generation means.

FIG. 17 schematically shows procedures of the prior tablet productionmethod disclosed in JP-B-41-11273.

FIG. 18 schematically shows procedure of the prior tablet productionmethod disclosed in JP-A-56-14098.

DISCLOSURE OF THE INVENTION

The tablet production method according to the present invention will bedetailed hereinafter referring to the attached drawings.

Here the present invention will be explained when a rotary typetabletting machine is used.

FIG. 1 shows schematic construction by enlarging one part around arotary table of a rotary type tabletting machine used for executing thepresent invention.

FIG. 2 is a schematic section when one part of FIG. 1 around the rotarytable is enlarged.

As shown in FIG. 1 and FIG. 2, the rotary type tabletting machine A iscomprised of a rotatably provided rotary table 2 having plural dies 1, .. . in circumferential direction, plural upper punches 3, . . . andplural lower punches 4, . . . provided so as to correspond to each dies1, . . . . A spraying chamber 8 is provided at P1 which is before apoint P2 where molding material is charged in the die 1. A pulsatingvibration air generation means 7 is connected to the spraying chamber 8and a spray nozzle 9 for spraying lubricant L is provided in thespraying chamber 8. In this embodiment, an air source 10 such as acylinder charging compressed air is connected to the spray nozzle 9 andlubricant L is designed to be sprayed from the spray nozzle 9 by the airgenerated from the source 10.

Next, tablet production procedure using this machine A will beexplained.

The rotary table 2 is rotated at a fixed speed, pulsating vibration airis generated in the spraying chamber 8 by driving the pulsatingvibration air generation means 7 when the die 1 comes to the point P1where the spraying chamber 8 is provided according to rotation of therotary table 2, lubricant L is simultaneously sprayed from the spraynozzle 9, and lubricant L is applied on an inner wall is of the die 1, alower surface 3 s of the upper punch 3, and an upper surface 4 s of thelower punch 4.

Then, molding material m is charged in the die 1 which comes to thepoint P2 for charging molding material m in the die 1 accompanied withrotation of the rotary table 2 and extra molding material m is removed.Thereafter, when the die 1 charged with molding material m comes to apoint P3 for compressing molding material m, molding material m in thedie 1 is compressed to produce a tablet by means of the upper punch 3 ofwhich lower surface 3 s is applied with lubricant L and the lower punch4 of which upper surface 4 s is applied with lubricant L. Further, whenthe die 1 comes to a point P4, a tablet T is discharged from the die 1so that the tablet T is produced.

FIG. 3( a) shows schematic construction around the spraying chamber 8and FIG. 3( b) illustrates construction by an example of pulsatingvibration air generation means 7.

In this example, the pulsating vibration air generation means 7 isconnected to the spraying chamber 8 via a conduit 13.

In FIG. 3( b) the numeral 71 shows a blower, 72 shows a cylindricaltube, 73 shows a valve element provided rotatably around a rotary axis74 so as to divide inside of the tube 72 into two parts. The conduit 13and a conduit 14 coupled to the blower 71 are connected at a given placeof the side of the tube 72. The valve element 73 is designed to berotated at a desired rotational velocity by means of a valve rotationcontrol means (not shown).

When the blower 71 is rotated at a given rotation number and the valveelement 73 is also rotated at a given rotation number, the sprayingchamber 8 and the blower 71 are connected as the valve element 73 ispositioned at a place shown by a solid line in the figure. When thevalve element 73 is positioned at a place shown by a dotted line, thespraying chamber 8 and the blower 71 are blocked off by the valveelement 73. Accordingly, pulsating vibration air with its peak atatmospheric pressure and its valley at negative pressure shown in FIG.4( a) or pulsating vibration air with its peak and valley at negativepressure shown in FIG. 4( b) can be produced in the spraying chamber 8.

Here “negative pressure” means that the pressure in the spraying chamber8 is lower than outside pressure (atmospheric pressure).

According to this tablet production method, because lubricant L isn'tincluded in the molding material m, produced tablet can obtain practicalhardness even if tabletting pressure is less than or equal to 1 ton/cm².Therefore, this method is suitable for producing a tablet includingcompound which is denaturalized or inactivated when tabletted at highpressure and a tablet including solid dispersion powdered or granulated.

When lubricant L is sprayed from the spray nozzle 9 while generatingpulsating vibration air shown in FIG. 4( a) or FIG. 4( b), sprayedlubricant L is diffused by the pulsating vibration air and attaches onthe inner wall 1 s of the die 1, the lower surface 3 s of the upperpunch 3 and the upper surface 4 s of the lower punch 4 both of which areprovided so as to correspond to the die 1 housed in the spraying chamber8.

According to this tablet production method, as lubricant L can beuniformly applied on the inner wall 1 s of the die 1, the lower surface3 s of the upper punch 3, and the upper surface 4 s of the lower punch4, molding material m can be prevented from adhering on the die 1, theupper punch 3, and the lower punch 4 of the tabletting machine A even ifthe amount of lubricant L sprayed in the spraying chamber 8 is only alittle.

Utilizing this, if the spray amount of lubricant L to be sprayed in thespraying chamber 8 is controlled to be greater than or equal to 0.0001weight % and less than or equal to 0.2 weight % per the weight oftablet, a part of lubricant L attached on the inner wall is of the die1, the lower surface 3 s of the upper punch 3, and the upper surface 4 sof the lower punch 4 is slightly attached only on the surface of theproduced tablet T so that the tablet T without including lubricant Ltherein can be produced.

As the result, the used amount of lubricant L for the tablet T isremarkably small comparing with the tablet produced by the priorproduction method. Therefore, a problem, which has been found in theprior tablet, wherein disintegration time of tablet delays because ofwater repellency of lubricant L is never happened.

Accordingly, if the tablet T produced according to the above-mentionedmethod is used as an uncoated tablet, it becomes a rapidly solubletablet and is suitable as a tablet which is required to be rapidlydisintegrated at an objected part like an intraorally rapidlydisintegrable tablet.

If a film coat which can be melted at an objective part is executed onthe surface of the tablet, the tablet is rapidly dissolved at anobjective part when the film coat is melted. Consequently, a tabletwhich can be dissolved at an objective part can be produced.

In this embodiment, the system shown in FIG. 3( b) is used as apulsating vibration air generation means 7, however, it is only anexample and any kinds of system can be used as the pulsating vibrationair generation means 7. For example, the blower 71 may be connected tothe end of the conduit 13, a solenoid valve may be provided in themiddle of the conduit 13 for opening and closing the conduit 13, theblower 71 may be rotated at a given rotation number so as to suck air inthe spraying chamber 8, and the conduit 13 may be opened or closed at aprescribed period by the solenoid valve. Otherwise the blower 71 may beconnected to the end of the conduit 13, the blower 71 may be rotatedfast or slowly at a given period, and air in the spraying chamber 8 maybe sucked strongly and weakly.

Also in the above-mentioned embodiment, the pulsating vibration airshown in FIG. 4( a) or FIG. 4( b) is generated. The system shown in FIG.5 may be constructed and the pulsating vibration air shown in FIG. 6( a)or FIG. 6( b) may be generated in the spraying chamber 8. Namely, in theembodiment shown in FIG. 5, a pulsating vibration air generation means7A is connected to the end of the conduit 13, a hopper 15 storinglubricant L is connected in midstream of the conduit 13, and acompressed air generation means 16 such as a cylinder chargingcompressed air is connected to the hopper 15 as shown in FIG. 5( a). Thenumeral 17 in FIG. 5( a) shows a blower provided if required. When theblower 17 is driven, air in the spraying chamber 8 is sucked andpulsating vibration air supplied in the spraying chamber 8 and lubricantL are induced to be discharged from the spraying chamber 8.

As shown in FIG. 5( b), the pulsating vibration air generation means 7Ais provided with the blower 71, the cylindrical tube 72 connected to theconduit 13 between the blower 71 and the hopper 15, and the valveelement 73 which is rotatable around the rotary axis 74 in the tube 72and is designed to divide the inside of the tube 72 into two parts. Theconduit 13 and the conduit 14 coupled to the blower 71 are connected tothe side of the tube 72. The valve element 73 is constructed so as to berotated at a desired rotational velocity by means of a valve rotationcontrol means (not shown).

When the blower 71 is rotated at a given rotation number to send air tothe spraying chamber 8 and the valve element 73 is also rotated at agiven rotational velocity, the spraying chamber 8 and the blower 71 areconnected when the valve element 73 is located at the place shown as aslid line in the figure. When the valve element 73 is located at adotted line, the spraying chamber 8 and the blower 71 are blocked off bythe valve element 73. Accordingly pulsating vibration air with its peakat positive pressure and its valley at atmospheric pressure as shown inFIG. 6( a) is generated in the spraying chamber 8. Otherwise, pulsatingvibration air with its peak and valley at positive pressure as shown inFIG. 6( b) may be generated in the spraying chamber 8. While keepingthis condition, the compressed air generation means 16 may be driven tofeed lubricant L contained in the hopper 15 to the conduit 13 and afixed amount of lubricant L may be supplied in the spraying chamber 8together with the current of pulsating vibration air.

Here positive pressure means that the pressure in the spraying chamber 8is higher than the pressure outside of the spraying chamber 8(atmospheric pressure).

Otherwise, the blower 71 may be provided at the end of the conduit 13,the solenoid valve for opening and closing the conduit 13 may be alsoprovided in the midstream of the conduit 13, the blower 71 may berotated at a given rotation number to feed air in the spraying chamber8, the conduit 13 may be opened and closed periodically, then pulsatingvibration air may be generated in the spraying chamber 8 and the conduit13. While keeping such a condition, the compression air generation means16 may be driven to feed lubricant L contained in the hopper 15 to theconduit 13 and a fixed amount of lubricant L is supplied in the sprayingchamber 8 together with the current of pulsating vibration air. On theother hand, the blower 71 may be connected at the end of the conduit 13,the blower 71 may be rotated fast or slowly at a given period so as tofeed air strongly or weekly in the spraying chamber 8, and pulsatingvibration air may be generated in the spraying chamber 8 and the conduit13. While keeping this condition, the compression air generation means16 may be driven so as to feed lubricant L contained in the hopper 15 tothe conduit 13 and a fixed amount of lubricant L may be supplied in thespraying chamber 8 together with the current of pulsating vibration air.

The present invention will be further explained based on concreteexperimental data.

(Experiment 1)

Here an example of producing tablet including powdered or granularcompound which is denaturalized or inactivated when tabletted at highpressure is shown.

Water solution of 15 w/v % lactose was mixed with water solution of 10w/v % serrapeptase in a ratio of 10 g serrapeptase to 50 g lactose. Themixture was frozen and dried under the condition wherein initialtemperature at −55° C. and pressure at 10⁻³ mmHg; final temperatureafter 27 hours at +60° C. and pressure at 10⁻¹ mmHg and then mixed,kneaded, dried, and sized. The powdered or granular material (averageparticle size: 60 μm) of which prescription is shown in table 1 isprepared.

TABLE 1 combined ingredient Prescription (mg) serrapeptase 5 mg lactose87 mg cornstarch 37.5 mg isopropanol 0.015 ml

Then using the rotary tabletting machine A provided with the pulsatingvibration air generation means 7 shown in FIG. 1, material wascontinuously tabletted by means of 7 mm diameter die and punch set at arotational velocity which rotates the rotary table 2 at 30 times perminute so as to produce the sized granulated material of 130 mg/tablet.

Magnesium stearate was used as lubricant and the used amount ofmagnesium stearate sprayed in the spraying chamber 8 was controlled suchthat weight % of the lubricant included per a produced tablet becomes0.03 weight %.

HATA HT-X20 by Hata Seisakusho Co., Ltd. was used as a main body of thetabletting machine A.

When the rotary type tabletting machine A provided with the pulsatingvibration air generation means 7 shown in FIG. 1 was used, it was foundthat the produced tablet has practical hardness at a tabletting pressureof 0.7 ton/cm².

The condition of pulsating vibration air isn't specifically limited.However, in this experiment, the period of pulsating vibration air wasgreater than or equal to 1 Hz and less than or equal to 10 Hz, itsvalley became 15%–5% lower than atmospheric pressure and also its peakbecame almost the same as or a little lower than atmospheric pressure.

(Comparison 1)

Magnesium stearate was added as lubricant for the powdered or granularmaterial used in the experiment 1 as shown in table 1 in a ration of 0.8weight % for the entire amount of a tablet. After they were well mixedby a V type mixer, they were continuously tabletted by an internallubricant method at a speed of rotating the rotary table at 30 times perminute by means of a set of 7 mm punch and die so as to produce thematerial into a 130 mg tablet.

HATA HT-X20 by Hata Seisakusho Co., Ltd. was used as the tablettingmachine A.

In this case it was found that the produced tablet didn't have practicalhardness at a tabletting pressure of 0.7 ton/c m².

(Comparison 2)

The powdered or granular material used in the experiment 1 as shown intable 1 was tabletted by means of a set of 7 mm punch and die so as toproduce a 130 mg tablet. Stearate magnesium was applied on the surfacesof the punch and die according to the method described in JP-B-41-11273so that the weight % of lubricant became 0.03 weight % per a producedtablet. Then the material was continuously tabletted at a speed ofrotating the rotary table 30 times per minute.

HATA HT-X20 by Hata Seisakusho Co., Ltd. was used as the tablettingmachine A.

Next, disintegration test according to Japanese Pharmacopoeia wasexecuted for three kinds of tablets produced according to the experiment1, the comparison 1, and the comparison 2 at a given test number (N=5).

The result is shown in Table 2.

TABLE 2 disintegration time average Tabletting measurement Pressurehardness (standard actual (ton/cm²) (kg) variation) measurementexperiment 0.7 7 3.0 3.0 1 (±0.2) 2.7 2.9 3.2 3.1 comparison 0.7 4 7.27.2 1 (±0.9) 7.8 8.3 6.4 6.2 comparison 0.7 7 4.0 4.1 2 (±0.6) 3.5 3.34.8 4.5

According to the table 2, it was found that the experiment had highhardness comparing with the comparison 1 and had ort disintegration timecomparing with the comparison 1 and And also its disintegration timedoesn't widely vary.

(Comparison 3)

Magnesium stearate was added as lubricant for the powdered or granularmaterial used in the experiment 1 as shown in the table 1 in a ratio of0.8 weight % for the entire amount of a tablet. After they were wellmixed by a V type mixer, they were continuously tabletted by an internallubricant method at a speed of rotating the rotary table 30 times perminute by means of a set of 7 mm punch and die so as to produce a 130 mgtablet.

In this case a tabletting pressure was 1.3 ton/cm² so that producedtablet has practical hardness.

Next, residual ratio of serrapeptase was measured for the experiment 1,the comparison 1, and the comparison 2. The result was the experiment1>the comparison 1>and the comparison 2.

Concretely explained, after the tablet including serrapeptase obtainedin the experiment 1, the comparison 1, and the comparison 2 werepreserved at 40° C. for three months, residual ratio of serrapeptase wasmeasured. The residual ratio of the experiment 1 was 98.8%, that of thecomparison 1 was 90.7%, and that of the comparison 2 was 87.9%.Accordingly, the tablet including serrapeptase produced according to thepresent invention had higher stability comparing with the tabletincluding serrapeptase produced according to the prior invention.

For each experiment 1, comparisons 1–3, material was continuouslytabletted for 5 hours and produced tablet was sampled with time. Timewhich didn't cause sticking was measured by smoothness of producedtablet surface. In the experiment 1, sticking wasn't happened after 5hours. However, in the comparison 1 and 3 sticking was happened after 1hour and in the experiment 2 sticking was happened after 2 hours.

Based on the above-mentioned results, a tablet produced according to thepresent invention can achieve practical hardness even if tablet isproduced at a tabletting pressure less than or equal to 1 ton/cm².Therefore, when the present tablet production method is applied forproducing tablet including drugs having inferior stability (for exampleactivity is deteriorated), the present invention can heighten stabilityof drugs included in tablet comparing with the tablet produced accordingto the prior art (for example there is no problem such as deterioratingactivity of drugs included in tablet).

Therefore, for example, when the tablet including many drugs as shown intables 3–5 is produced, the tablet production method according to thepresent invention is effective.

TABLE 3 1.Antipyretics, Indometacin, Dicrofenac sodium, Ibuprofen,Analgesics, Asprin, Dexamethasone, Prednisolone, Antiinflammatory agentsLoxoprofen sodium, Ketoprofen, Serrapeptase, Lysozyme Chloride,Streptokinaze, Salicylamide 2.Antacid, Famotidine, Sucralfate,Cimetidine, Antiulcers Aceglutamide aluminium, Dried aluminium hydroxidegal, Sodium bicarbonate, Diastase, Sodium copper chlorophyllin,L-glutamine, Sodium alginate 3.Antihypertensives, Benidipinehydrochloride, nifedipine, Cardiovascular agents nicardipinehydrochloride, amlodipine besylate 4.Antibiotics Amoxicillin,Ampicillin, Minocycline hydrochloride, 5.Antitussives, Theophylline,Methlyephedrine hydrochloride, Antiasthma agents, Sodium cromoglicate,Salbutamol sulfate, Bronchodialators Codeine phosphate 6.DiureticsFurosemide, Chlorothiazide, Spironolactone 7.Tranquilizers Diazepam,Chlorpromazine, Haloperidol, Bromperidol, Risperidone 8.AntipodagricsAllopurinol, Probenecid 9.Anticoagulants Warfarin, Heparin sodium,Alteplase, Urokinase, tisokinase 10.Blood coagulants Blood coagulantfactor VIII, Active prothombine complex 11.Erythropoietins Epoetin β,Epoetin α 12.Hypolipidemics Pravastatin sodium, Simvastatin,Bezafibrate, Tocopherol nicotinate, Dextran sulfate sodium 13.Cerebralvasodilators, Nicergol, Ibudilast, Citicoline, Flunarizine Peripheralvasodilators hydrochloride 14.Calcitonins Elcatonin, Salmoncalcitonin(synthetic) 15.Anticonvulsants Phenytoin, Sodium propylvalerate, Carbamazepine, Zonisamide

TABLE 4 16.Antiemetics Metoclopramide, Donpridone, Cisapride17.Expectorants Bromhexine hydrochloride, Carbocisteine, Cysteineethylester hydrochloride, Ambroxol hydrochloride 18.AntidiabetesGlibenclamide, Tolbutamide, Insulin, Glucagon - like insulintropicpeptide 19.Cardio vascular Ubidecarenon, ATP-2 sodium, Nitroglycerin,agents Isosorbide didinirate 20.Vitamins Vitamin A, Vitamin B, VitaminC, Vitamin D, Folic acid 21.Antipollakisurias Flavoxate hydrochloride,Oxybutynin Antiduretic hormones hydrochloride, Desmopressin acetate,Vasopressin 22.Ace inhibitors Enalapril maleate, Alacepril23.Antiparkinsonism Droxidopa, Pergolide mesilate, levodopa, carbidopa24.Digestives Pancreatic digestive enzyme, Sanactase combined drug,Gastric mucosa extraction drug, Tilactase 25.Anticancer agents Tegaful,Fluorouracil, Doxifluridine, Methotrexate, Etoposide, Vindesine sulfate,Epirubicin hydrochloride, L-asparaginase, Leuprorelin acetate, Goserelinacetate, Chlormadinone acetate, Tamoxifen citrate, Filgrastim,Lenograstim, nartograstim, Lentinan, Interferon 26.ImmunosuppressorCyclosporin, Mizoribine, Immunoglobulin 27.Anesthesias Lidocainehydrochloride, Procaine hydrochloride, morphine sulfate, Buprenorphinehydrochloride, Pentazocine, Fentanyl 28.Sedatives Brotizolam, Triazolam,Flunitrazepam, Flurazepam hydrochloride 29.Nootropics Idebenone,Propentofylline, Indeloxazine hydrochloride, Bifemelane hydrochloride,

TABLE 5 30.Antiallergies Beclometasondipropionat, Ketotifen fumarate,Amlexanox, Terfenadine, Azelastin hydrochloride, Tranist, Olopatadine,Oxatomide, Epinastine hydrochloride, Astemizole 31.Diagnostics,[¹³C]Urea, Glucagon, Partially hydolyzed Other therepeutic agentsstarch, Prostaglandin, Leukotriene, Thromboxan A2, Platelet activatingfactors, insulinnoid growth factors, Neurone growth factors, Epidermalgrowth factors, Vascular endothelial growth factors, Ribonucleic acid,Deoxyribonucleic acid, Oligonucleoside, Ttrehalose, Dextran, Chitin,Acacia, Agar, Chondroitin sulfuric acid, Hyaluronic acid, Cyclodextrin,β glucan, Trypsin, Chymotrypsin, Pepsin, Aprotinin, Bestatin,Mumpsvaccine, Poliovaccine

Further, it was found that sticking and so on were hardly caused whentabletting.

(Experiment 2)

Here an example of producing a tablet including solid dispersionpowdered or granulated.

2500 g of hydroxypropylmethylcellulose acetate succinate (brand name: Acoat, AS-MP, Shinetsu Kagaku Kogyo Co., Ltd.) was mixed with 500 g oforiginal powder (average particle size 60 μm) made by grindingdonperidone. Thereafter, processing treatment was executed by means of adual axis extruder equipped with dies of 4 mmø×2 caliber (KEX-25:Kurimoto Tekkosho Co., Ltd.) at 100° C. barrel temperature at extrudingspeed of 200 rpm while adding a little water, thereby solid dispersionwas obtained.

Thus obtained solid dispersion was minutely ground by a sample mill(type: AP-S, Hosokawa Tekkosho Co., Ltd.).

Next, such solid dispersion was tabletted by a tabletting machine withan external lubricant spraying means A as follows. The punches 3, 4 andthe die 1 were housed in the spraying chamber 8, magnesium stearate wasapplied as lubricant L on the surfaces of 3 s, 4 s of the punches 3, 4and the surface is of the die 1 by generating pulsating vibration air asshown in FIG. 4( a) in the spraying chamber 8. The substance wascontinuously tabletted by means of the punches 3, 4 and the die 1 onwhich surfaces 3 s, 4 s, 1 s were applied with magnesium stearate at aspeed of rotating the rotary table at 30 times per minute.

The conditions of pulsating vibration air isn't limited. However in thisexample, period of pulsating vibration air was more than or equal to 1Hz and less than or equal to 10 Hz, the valley thereof was set at about10% lower than atmospheric pressure, and the peak thereof was equal toor a little less than atmospheric pressure.

Next, solubility test of thus obtained tablet of solid dispersion andpowder X-ray diffraction test (250 mesh passing) were executed.

(Comparison 4)

2500 g of hydroxypropylmethylcellulose acetate succinate (brand name: Acoat, AS-MP, Shinetsu Kagaku Kogyo Co., Ltd.) was mixed with 500 g oforiginal powder (average particle size 60 μm) made by grindingdonperidone. Thereafter, processing treatment was executed by means of adual axis extruder equipped with dies of 4 mmø×2 caliber (KEX-25:Kurimot Tekkosho Co., Ltd.) at 100° C. barrel temperature at extrudingspeed of 200 rpm while adding a little water, thereby solid dispersionwas obtained.

Thus obtained solid dispersion was minutely ground by a sample mill(type: AP-S, Hosokawa Tekkosho Co., Ltd.) and solubility test of thusobtained minute particle and powder X-ray diffraction test (250 meshpassing) were executed.

As a result, the experiment 2 and the comparison 4 showed almost thesame solubility and it was found that crystal peak of donperidone ofboth cases were disappeared.

For the experiment 2 and the comparison 4, material was continuouslytabletted for 5 hours and tablets were sampled with time, then timewithout happening sticking was measured by smoothness of the producedtablets. Sticking wasn't seen after 5 hours in the experiment 2, howeverin the comparison 4, sticking was already seen after 1 hours.

Several kinds of solid dispersion was produced for the several drugsshown in the tables 3–5 by means of a dual axis type extruder andsimilar tests as the experiment 2 and the comparison 4 were executed.

The punches 3, 4 and the die 1 were housed in the spraying chamber 8,magnesium stearate was applied as lubricant L on the surfaces of 3 s, 4s of the punches 3, 4 and the surface is of the die 1 by generatingpulsating vibration air as shown in FIG. 4( a) in the spraying chamber8. The substance was continuously tabletted by means of the punches 3, 4and the die 1 on which surfaces 3 s, 4 s, is were applied with magnesiumstearate at a speed of rotating the rotary table at 30 times per minute.It was found that thus obtained tablet and minute particles obtained bygrinding the solid dispersion by a sample mill had almost the samesolubility and crystal peak of both of them were disappeared.

According to the above-mentioned results, it was found that the tabletproduction method according to the present invention could be preferablyused for producing a tablet of solid dispersion.

Next, several anomalous tablets shown in FIGS. 7–11 were producedsimilar to the experiment 1, 2, however a punch and a die comprising afemale mold of tablet.

The tablet in FIG. 7( a) shows a circular tablet generally called flatplain, the tablet in FIG. 7( b) shows a circular tablet generally calledshallow concave plain, the tablet in FIG. 7( c) shows a circular tabletgenerally called normal concave plain, the tablet in FIG. 7( d) shows acircular tablet generally called deep concave plain, tablet in FIG. 7(e) shows a circular tablet generally called ball or pill, tablet in FIG.7( f) shows a circular tablet generally called flat beveled edge.

The tablet in FIG. 8( a) shows a circular tablet generally called doubleradius, the tablet in FIG. 8( b) shows a circular tablet generallycalled bevel and concave, the tablet in FIG. (8 c) shows a circulartablet generally called ring, the tablet in FIG. 8( e) shows a acircular tablet generally called rim, and the tablet in FIG. 8( f) showsa capsule type tablet generally called capsule.

The tablet in FIG. 9( a) shows a circular tablet generally called oval,the tablet in FIG. 9( b) shows an elliptical tablet generally calledellipse, the tablet in FIG. 9( c) shows a rectangular tablet generallycalled square, the tablet in FIG. 9( d) shows a triangular tabletgenerally called triangle, the tablet in FIG. 9( e) shows a pentangulartablet generally called pentagon, and the tablet in FIG. 9( f) shows ahexagonal tablet generally called hexagon.

The tablet in FIG. 10( a) shows a heptagonal tablet generally calledheptagon, the tablet in FIG. 10( b) shows a octagonal tablet generallycalled octagon, the tablet in FIG. 10( c) shows a diamond-shaped tabletgenerally called diamond, the tablet in FIG. 10( d) shows apillow-shaped tablet generally called pillow or barrel, the tablet inFIG. 10( e) shows a rectangular tablet generally called rectangle, andthe tablet in FIG. 10 f) shows an almond-shaped tablet generally calledalmond.

The tablet in FIG. 11( a) shows a sagittal tablet generally calledarrowhead, the tablet in FIG. 11( b) shows a bullet-shaped tabletgenerally called bullet, the tablet in FIG. 11( c) shows a semilunartablet generally called half moon, the tablet shown in FIG. 11( d) showsa shell-shaped tablet generally called shelled, the tablet in FIG. 11(e) shows a heart-shaped tablet generally called heart, and the tablet inFIG. 11( f) shows a star-shaped tablet generally called star.

Material was continuously tabletted for 5 hours by means of punches anddies comprising a female mold for the tablets shown in FIG. 7–FIG. 11,obtained tablets were sampled with time, and time for causing stickingwas measured by smoothness of the produced tablet's surface. The resultwas that sticking wasn't happened even after 5 hours.

From the above-mentioned results, it was found that the tabletproduction method according to the present invention can be preferablyused for producing anomalous tablets other than circular tablets.

For tablets using an engraved mark or a dividing line, several dividabletablets were produced like the experiments 1 and 2 except that puncheswith a projected line for forming a dividing line were used.

Material was continuously tabletted for 5 hours, the produced tabletswere sampled with time, and time for happening sticking was measured bysmoothness of tablets' surfaces. Sticking wasn't seen even after 5hours.

Negative pulsating vibration air was used in the above-mentionedexperiments. However, pulsating vibration air isn't limited to negativeone. When positive pulsating vibration air is used, similar result canbe obtained.

In this case, conditions of positive pulsating vibration air aren'tspecifically limited. The period may be more than or equal to 1 Hz andless than or equal to 10 Hz, its peak may be 10%–15% higher thanatmospheric pressure, and its valley may be almost equal to or a litterhigher than atmospheric pressure.

In the disclosure of the invention, a system wherein the hopper 15 isconnected in midway of the conduit 13 and the compressed air generationmeans 16 such as a cylinder fully charged with compressed air isconnected to the hopper 15 as shown in FIG. 5 is explained. However, thesystem for discharging lubricant L stored in the hopper 15 to theconduit 13 isn't limited to such a system.

FIG. 12 explains such a system schematically.

According to the system, a pulsating vibration air generation means 7Ais connected to one end 13 a of the conduit, a discharge port 15 a ofthe hopper 15 is connected in midway of the conduit 13, and an elasticmembrane 18 with an aperture (slit in this example) 18 a is provided atthe discharge port 15 a so as to be a bottom of the hopper 15 (see FIG.13).

The elastic membrane 18 is made of rubber such as silicon rubber.

The member shown as 15 b in the FIG. 12 is a lid and is provided for thehopper 15 removably and airtightly.

Next, operations of the system will be explained.

FIG. 14 is an explanatory figure schematically showing operation of thesystem.

For using the system, the lid 15 b is airtightly attached on the hopper15 after lubricant L is contained in the hopper 15.

Then, when the pulsating vibration air generation means 7A is driven tosupply positive pulsating vibration air to the conduit 13, the airpressure in the conduit 13 becomes higher than that in the hopper 15while positive pulsating vibration air is at peak side. As shown in FIG.14( a), the elastic membrane 18 is deformed with its center curvedupwardly in such a manner that the center becomes an antinode and thecircumferential edge becomes a node.

In this case, the section of the aperture (slit in this example) 18 abecomes V-shaped with is upper end opened. A part of lubricant L storedin the hopper 15 drops in the V-shaped aperture (slit in this example)18 a.

As positive pulsating vibration air changes from peak to valley, the airpressure in the conduit 13 is generally lowered so as to be the same asthat in the hopper 15. The elastic membrane 18 is going to get back toits original shape because of its resilience as shown in FIG. 14( b).The lubricant L dropped in the V-shaped aperture (slit in this example)18 a is caught in the aperture 18 a.

When the positive pulsating vibration air supplied in the conduit 13 isat its valley, the air pressure in the conduit 13 becomes lower thanthat in the hopper 15 and the elastic membrane 18 is deformed with itscenter curved downwardly in such a manner that the center is antinodeand the circumferential edge is node.

In this case, the section of the aperture (slit in this example) 18 abecomes reverse V-shaped with its lower end opened. The lubricant Lcaught in the aperture 18 a is discharged to the conduit 13.

Then the lubricant L discharged in the conduit 13 is immediately mixedwith positive pulsating vibration air supplied in the conduit 13 to bedispersed in the conduit 13 and is pneumatically transported to aspraying chamber (refer to the spraying chamber 8 in FIG. 5).

The elastic membrane 18 repeats up and down vibration as shown in FIG.14( a)–FIG. 14( c) according to vibration amplitude, wave length, waveshape, and vibration frequency of positive pulsating vibration air.

Therefore, as long as vibration amplitude, wave length, wave shape, andvibration frequency of positive pulsating vibration air supplied in theconduit 13 are fixed, the elastic membrane 18 vibrates up and down at afixed vibration amplitude and frequency. Accordingly the amount oflubricant L discharged in the conduit 13 via the aperture (slit in thissample) 18 a is constant.

Further according to this system, because positive pulsating vibrationair is supplied in the conduit 13, there are no phenomenon such asadhesion of powdered material on the inner wall of the conduit 13 andblowing-out of powdered material in the conduit 13 which have been seenin the case that steady air pressure is used for pneumaticallytransporting powdered material.

Therefore, according to this system, lubricant L is discharged from theother end 13 b of the conduit 13 at the same density as the lubricant Ldischarged in the conduit 13.

In other words this system can be functioned as a metering feeder.

Therefore, when the other end 13 b of the conduit 13 is connected to thespraying chamber (refer to spraying chamber 8 in FIG. 5), as long as thesize of the aperture (slit in this example) 18 a is fixed, and vibrationamplitude, wave length, wave shape, and vibration frequency of positivepulsating vibration air supplied in the conduit 13 are fixed, lubricantL with constant density can be always supplied in the spraying chamber(refer to spraying chamber 8 in FIG. 5).

Further, a media for pneumatically transporting lubricant L is air evenif it is a positive pulsating vibration air so that the amount oflubricant L mixed with positive pulsating vibration air can be extremelyminimized.

Accordingly, because a minute amount of lubricant L can be alwayssprayed in stable condition in the spraying chamber (refer to sprayingchamber 8 in FIG. 5), minute amount of lubricant L can be applied on thesurfaces of the punches (the surface (lower surface) 3 s of the upperpunch and the surface (upper surface) 4 s of the lower punch 4 as shownin FIG. 2) and the surface (inner wall) is of the die 1.

In FIG. 12, the elastic membrane has a slit 18 a, however, this is onlya preferable example. The aperture provided for the elastic membraneisn't limited to the slit 18 a and the aperture may be small ones or thenumber isn't limited to one.

When the size and the number of the aperture or conditions (vibrationamplitude, wave length, wave shape, and vibration frequency) of positivepulsating vibration air supplied in the conduit 13 are varied, thedensity of lubricant L supplied in the spraying chamber (refer to thespraying chamber 8 in FIG. 5) can be changed diversely.

In this embodiment, a rotary type pulsating vibration air generationmeans 7A shown in FIG. 3( b) and FIG. 5( b) wherein a valve element 73is provided rotatably around a rotary axis 74 so as to divide inside ofthe tube 72 into two parts is explained as a pulsating vibration airgeneration means. However, it isn't limited to such means 7A.

FIG. 16 shows a section of other embodiment of pulsating vibration airgeneration means.

The high pressure pulsating vibration air generation means 7B isprovided with a valve chamber 94 having a valve seat 94 between an inputport 91 and an output port 92 and a valve plug 96 which opens and closesby a cam mechanism 95.

The cam mechanism 95 is provided with a rotary cam 97 rotatable by adriving means such as a motor (not shown) and a roller 98 attached atthe lower end of the valve plug 96.

The valve seat 93 is formed with a hole narrowing into the output port92 and the valve plug 96 is formed like a reverse mortar so as toconform to the shape of the valve seat 93 and designed to airtightlyclose the valve seat 93.

Further in this embodiment, an axis 96 a of the valve plug 96 isprovided in an axis hole 99 h of a case 99 so as not to leak air and soas to be movably up and down.

The roller 98 is rotatably pinched by the rotary cam 97 and moves up anddown according to a concavo-convex pattern on the rotary cam 97 whilerotating.

More detailed, the rotary cam 97 is provided with an inner rotary cam 97a and an outside rotary cam 97 b.

Concavo-convex pattern is provided for the inner rotary cam 97 a and theoutside rotary cam 97 b respectively so as to keep distance of theroller 98 and to keep in line each other.

The roller 98 is pinched between the inner rotary cam 97 a and theoutside rotary cam 97 b and is moved up and down while rotatingaccording to the concavo-convex pattern provided for the inner rotarycam 97 a and the outside rotary cam 97 b by rotating the rotary cam 97without causing jumping of the valve plug 96.

The convavo-convex pattern provided for the rotary cam 97 is selectedaccording to physical property of lubricant L stored in the hopper 15.

In this embodiment, a flow rate control means 102 is provided for theinput port 91 and compressed air which is generated by an air source 71and of which flow rate is adjusted properly by the flow rate controlmeans 102 is supplied in the input port 91.

Further, one end of a conduit (the conduit 13 shown in FIG. 3 or FIG. 5)is connected to the output port 92.

The numeral 100 in FIG. 5 shows a flow rate control port provided ifrequired. An output control valve 101 for adjusting pressure ofpulsating vibration air generated from the output port 92 is provided soas to be adjustable at a desired condition from full communication toatmospheric air and shut down from atmospheric air.

Next, operational procedure for generating positive pulsating vibrationair having a desired period, vibration amplitude, and wave shape bymeans of the high pressure pulsating vibration air generation means 7Bwill be explained.

The rotary cam 97 which is easy to mix lubricant L with air according tophysical property of lubricant L stored in the hopper 15 is attached toa rotary axis Ma of a driving means (not shown) of the high pressurepulsating vibration air generation means 7B.

Then the air source 71 is driven and a fixed amount of compressed air issupplied to the input port 92 by adjusting the flow rate control means102.

Further, the rotary cam 97 is rotated at a fixed rotational velocity byactuating the driving means (not shown).

The pressure of pulsating vibration air discharged from the output port92 is adjusted by adjusting the output control valve 101, if required.

When the rotary cam 97 is rotated at a fixed rotational velocity, thevalve plug 96 moves up and down according to the concavo-convex patternof the rotary cam 97. Therefore, when the valve seat 93 is controlled atfull closed, half opened, or full opened according to the concavo-convexpattern of the rotary cam 97, pulsating vibration air with a desiredwave shape can be outputted from the output port 92.

According to the high pressure pulsating vibration air generation means7B, rotational velocity of the rotary cam 97 may be changed bycontrolling the driving means (not shown) in order to obtain a desiredperiod of pulsating vibration air discharged from the output port 92.Further, the air source 71, the flow rate control means 102, and/or theoutput control valve 101 may be appropriately controlled in order toobtain a desired vibration amplitude of pulsating vibration airdischarged from the output port 92.

INDUSTRIAL APPLICABILITY

As mentioned above, according to the tablet production method as setforth in claim 1, as lubricant is sprayed in a spraying chambergenerating pulsating vibration air and lubricant mixed with pulsatingvibration air is applied on the surfaces of punches and dies, lubricantcan be uniformly applied on the surfaces of punches and dies comparingwith the prior external lubricant spraying method.

As a result, in a process of tabletting compound powdered or granulatedwhich is denaturalized or inactivated when tabletted at high pressure,compound powdered or granulated which is denaturalized or inactivatedwhen tabletted at high pressure is hard to be attached on the surfacesof punches and dies and also sticking, capping, laminating, and so onare hardly happened for the produced tablets of biologicalpharmaceuticals.

Further, lubricant is only attached on the surfaces of tablets and isn'tincluded inside therein. So, comparing with the tablet includinglubricant therein, when compound powdered or granulated which isdenaturalized or inactivated when tabletted at high pressure istabletted at a low tabletting pressure (concretely at tablettingpressure less than 1 ton/cm²), the produced tablet has practicalhardness.

According to the tablet production method as set forth in claim 2, aslubricant is sprayed in a spraying chamber generating pulsatingvibration air and lubricant mixed with pulsating vibration air isapplied on the surfaces of punches and dies, lubricant can be uniformlyapplied on the surfaces of punches and dies comparing with the priorexternal lubricant spraying method.

As a result, in a process of tabletting solid dispersion powdered orgranulated, molding material is hard to be adhered on the surfaces ofpunches and dies and also sticking, capping, laminating, and so on arehardly happened for the produced tablets of solid dispersion.

Further, lubricant is only attached on the surfaces of produced tabletsof solid dispersion and isn't included inside therein. So, comparingwith the tablet of solid dispersion including lubricant therein, whensolid dispersion powdered or granulated is tabletted at a low tablettingpressure, the produced tablet of solid dispersion has practicalhardness.

Therefore, according to this tablet production method, a tablet of soliddispersion can be produced at low tabletting pressure so that physicalproperty of solid dispersion doesn't change.

According to the tablet production method as set forth in claim 3, aslubricant mixed with positive pulsating vibration air is sprayed in aspraying chamber to be applied on the surfaces of the punches and dies,lubricant can be uniformly applied thereon comparing with the priorexternal lubricant spraying method.

As a result, in a process of tabletting compound powdered or granulatedwhich is denaturalized or inactivated when tabletted at high pressure,compound powdered or granulated which is denaturalized or inactivatedwhen tabletted at high pressure is hard to be attached on the surfacesof punches and dies and also sticking, capping, laminating, and soon arehardly caused for the produced tablets of biological pharmaceuticals.

Further, lubricant is only attached on the surfaces of tablets and isn'tincluded inside therein. So, comparing with the tablet includinglubricant therein, when compound powdered or granulated which isdenaturalized or inactivated when tabletted at high pressure istabletted at a low tabletting pressure (concretely at tablettingpressure less than 1 ton/cm²), the produced tablet has practicalhardness.

According to the tablet production method as set forth in claim 4, aslubricant mixed with positive pulsating vibration air is sprayed in aspraying chamber to be applied on the surfaces of punches and dies,lubricant can be uniformly applied thereon comparing with the priorexternal lubricant spraying method.

As a result, in a process of tabletting solid dispersion powdered orgranulated, molding material is hard to be adhered on the surfaces ofpunches and dies and also sticking, capping, laminating, and so on arehardly caused for the produced tablets of solid dispersion.

Further, lubricant is only attached on the surfaces of produced tabletsof solid dispersion and isn't included inside therein. So, comparingwith the tablet of solid dispersion including lubricant therein, whensolid dispersion powdered or granulated is tabletted at a low tablettingpressure, the produced tablet of solid dispersion has practicalhardness.

Therefore, according to this tablet production method, tablet of soliddispersion can be produced at low tabletting pressure so that physicalproperty of solid dispersion doesn't change.

According to the tablet production method as set forth in claim 5, thespraying amount of lubricant per tablet is greater than or equal to0.0001 weight percent and less than or equal to 0.2 weight percent.Therefore, disintegrating time of tablet doesn't extend or its hardnessisn't deteriorated.

According to the tablet production method as set forth in claim 6, asthe punches are provided with a projected line for forming a dividingline of a tablet, a dividable tablet including compound powdered orgranulated which is denaturalized or inactivated when tabletted at highpressure and a dividable tablet including solid dispersion powdered orgranulated of which functions aren't damaged can be easily produced.

According to the tablet production method as set forth in claim 7, asmaterial is continuously tabletted at tabletting procedure by utilizingthat sticking and so on aren't happened, a tablet including powdered orgranular compound which is denaturalized or inactivated when tablettedat high pressure can be produced at industrial production base.

According to the tablet production method as set forth in claim 8, asmaterial is continuously tabletted at tabletting procedure by utilizingthat sticking and so on aren't happened, tablet including soliddispersing powdered or granular material can be produced at industrialproduction base.

According to the tablet production method in claim 9, as the tablettingpressure for molding material is low, even if granule included in atablet is powdered or granular material including compound which isdenaturalized or inactivated when tabletted at high pressure, tablet canbe produced without denaturalizing or deactivating the compound.

Further, if granule included in a tablet is solid dispersion powdered orgranulated, a tablet can be produced without destroying functions ofsolid dispersion powdered or granulated.

According to the tablet in claim 10, as lubricant is attached only onthe surface of the tablet, disintegrating time of the tablet caused bywater repellency of lubricant doesn't delay.

Further, as this tablet doesn't include lubricant therein, it istabletted at low tabletting pressure. Therefore, compound powdered orgranulated which is denaturalized or inactivated when tabletted at highpressure isn't denaturalized or inactivated.

According to the tablet described in claim 11, as lubricant is onlyattached on the surface of the tablet, delay of disintegrating time ofthe tablet caused by water repellency of lubricant isn't happened.

Further, as this tablet doesn't include lubricant therein, it istabletted at low tabletting pressure. Therefore, functions of soliddispersion powdered or granulated isn't damaged.

According to the tablet described in claim 12, only a minute amount oflubricant is attached on the surface of the tablet, disintegrating timeof the tablet caused by water repellency of lubricant doesn't delay.

Therefore, if such a tablet (uncoated tablet) is used as an uncoatedtablet, it becomes a rapidly soluble tablet. It is suitable as a tabletwhich is desired to be disintegrated immediately at an objective place.If a film which is dissolved at an objective place is coated on thesurface of the tablet, the tablet can be rapidly dissolved at theobjective place when the film is melted. Therefore, such a tablet can beused as a tablet which is desired to be dissolved at an objective place.

According to the tablet as set forth in claim 13, as the shape of thetablet is anomalous, drugs (active agent) included in tablets can beeasily distinguished from the shape. As a result, medication error ishardly caused for these tablets.

According to the tablet as set forth in claim 14, as a dividing line isprovided for the surface of the tablet, dividable tablet which can bedissolved at an objective place can be supplied in the market.

1. A method for producing compressed tablets, comprising: selectingpowdered or granular material comprising an active compound which isdenaturalized or inactivated when compressed at a pressure greater thanor equal to 1 ton/cm², providing a spraying chamber housing a punch anda die, generating pulsating vibration air, spraying, within a sprayingchamber, a lubricant admixed with said pulsating vibration air to applythe lubricant on surfaces of said punch and die, mixing said powdered orgranular material with a diluting agent to make a molding material, saidmolding material not containing said lubricant, and compressing saidmolding material using said lubricated punch and said lubricated diesurfaces at a pressure less than 1 ton/cm² to produce compressedtablets, wherein sprayed lubricant is incorporated in said tablets at anamount not less than 0.0001 weight percent and not greater than 0.2weight percent.
 2. A method for producing compressed tablets,comprising: selecting powdered or granular material containing adispersed active agent, said active agent being a low molecule compoundof which elution is delayed when compressed at a pressure greater thanor equal to 1 ton/cm² or a high molecule compound which is decomposed ordenaturalized when compressed at a pressure greater than or equal to 1ton/cm², providing a spraying chamber housing a punch and a die,generating pulsating vibration air, spraying, within said sprayingchamber, a lubricant admixed said pulsating vibration air to apply thelubricant on surfaces of said punch and die, mixing said powdered orgranular material with said diluting agent to make a molding material,said molding material not containing said lubricant, and compressingsaid molding material using said lubricated punch and die surfaces at apressure less than 1 ton/cm² to produce compressed tablets, wherein thesprayed lubricant is incorporated in said tablets at an amount not lessthan 0.0001 weight percent and not greater than 0.2 weight percent.
 3. Amethod for producing compressed tablets, comprising: selecting powderedor granular material comprising an active compound which isdenaturalized or inactivated when compressed at a pressure greater thanor equal to 1 ton/cm², providing a spraying chamber housing a punch anda die, applying lubricant on surfaces of said punch and die by spraying,within said spraying chamber, an admixture of the lubricant and positivepulsating vibration air, mixing said powdered or granular material witha diluting agent to make a molding material, said molding material notcontaining said lubricant, and compressing said molding material usingsaid lubricated punch and said lubricated die surfaces at a pressureless than 1 ton/cm² to produce compressed tablets, wherein the sprayedlubricant is incorporated in said tablets at an amount not less than0.0001 weight percent and not greater than 0.2 weight percent.
 4. Amethod for producing compressed tablets, comprising: selecting powderedor granular material containing a dispersed active agent, said activeagent being a low molecule compound of which elution is delayed whencompressed at a pressure greater than or equal to 1 ton/cm² or a highmolecule compound which is decomposed or denaturalized when compressedat a pressure greater than or equal to 1 ton/cm², providing a sprayingchamber housing a punch and a die, applying the lubricant on surfaces ofsaid punch and die by spraying, within said spraying chamber, anadmixture of the lubricant and positive pulsating vibration air, mixingsaid powdered or granular material with a diluting agent to make amolding material, said molding material not containing said lubricant,and compressing said molding material using said lubricated punch andsaid lubricated die surfaces at a pressure less than 1 ton/cm² toproduce compressed tablets, wherein the sprayed lubricant isincorporated in said tablets at an amount not less than 0.0001 weightpercent and not greater than 0.2 weight percent.
 5. The method accordingto any one of claims 1–4, wherein said lubricant is stearate acid metalsalt.
 6. The method according to any one of claims 1–4, wherein saidlubricated surface of said punch is provided with a projecting line thatforms a dividing line on said tablets.
 7. The method according to any ofclaims 1–4 wherein said pulsating vibration air is generated, saidlubricant is admixed with said pulsating vibration air, and said mixtureof lubricant and pulsating vibration air is sprayed into said sprayingchamber simultaneously.
 8. The method according to any one of claims1–4, wherein said diluting agent is a saccharide.
 9. A tabletcomprising: powdered or granular material including an active compoundwhich is denaturalized or inactivated when compressed at a pressuregreater than or equal to 1 ton/cm², a diluting agent, and a lubricant,said tablet having been compressed at a pressure less than 1 ton/cm² andcontaining a tabletting lubricant only on a surface thereof and notwithin said tablet, said tabletting lubricant being contained in anamount not less than 0.0001 weight percent and not greater than 0.2weight percent, and wherein the active compound in said tablet hashigher activity than active compound in a tablet of same materialscompressed at same pressure but which contains said lubricant within thetablet.
 10. A tablet comprising: (i) powdered or granular materialcontaining a dispersed active agent, said active agent being a lowmolecule compound of which elution is delayed when compressed at apressure greater than or equal to 1 ton/cm² or a high molecule compoundwhich is decomposed or denaturalized when compressed at a pressuregreater than or equal to 1 ton/cm², (ii) a diluting agent, and (iii) alubricant, said tablet having been compressed at a pressure less than 1ton/cm² and containing a tabletting lubricant only on a surface thereofand not within said tablet, said tabletting lubricant being contained inan amount not less than 0.0001 weight percent and not greater than 0.2weight percent, and wherein the active compound in said tablet hashigher activity than active compound in a tablet of the same materialscompressed at same pressure but which contains said lubricant within thetablet.
 11. The tablet as set forth in claim 9 or 10, wherein the tablethas a dividing line on a surface thereof.
 12. The method according toany of claims 1–4, wherein said tablets have a hardness of at least 7kgf.
 13. The tablet according to either of claim 9 or 10, which have ahardness of at least 7 kgf.
 14. The tablet according to either of claim9 or 10, wherein said tabletting lubricant is stearate acid metal salt.